A kind of synthetic method of clofarabine
A synthesis method and clofarabine technology, which are applied in chemical instruments and methods, bulk chemical production, sugar derivatives, etc., can solve the problems of high product cost, long reaction time, low yield, etc., and achieve low total cost, Easy to handle, small particle size effect
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Embodiment 1
[0044] Example 1: Preparation of 1-bromo-2-deoxy-2-fluoro-3,5-tribenzoyl-α-D-arabinofuranose (compound I, R 1 and R 2 for benzoyl)
[0045]Add 28g of 2-deoxy-2-fluoro-1,3,5-tribenzoyl-α-D-arabinofuranose, 200mL of dichloromethane, and 36mL of hydrobromic acetic acid solution (33%) into a 500mL three-necked reaction flask , airtight, react at room temperature overnight, TLC monitoring, the reaction is completed, add 200mL ice water and stir for 15min, stand to separate layers, the organic layer is washed with 200mL×2 saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate for 2h, concentrated to dryness to obtain 24.0 g of compound III (94% yield).
Embodiment 2
[0046] Example 2: Preparation of 2,6-dichloro-9-(3′,5′-di-O-benzoyl-2′-fluoro-β-D-arabinofuranosyl)-purine (compound III)
[0047] After dissolving 24.0 g of the compound prepared in Example 1 in 200 mL of dichloromethane solution, transfer it to a 500 mL three-necked flask, add 200 mL of acetonitrile, and put in 10.0 g of 2,6-dichloropurine in turn under nitrogen protection, and put the catalyst into In the reaction flask, stir at room temperature for 12-16h. TLC: Ethyl acetate: Petroleum ether = 1:4, the reaction is complete, filter, wash the filter cake with a small amount of dichloromethane, adjust the pH of the filtrate to 6-8 with glacial acetic acid, filter again if there is precipitation, concentrate the mother liquor to dryness, add 40 mL of ethyl acetate Heat the ester to dissolve, add 40mL of methanol while it is hot, cool and crystallize, cool down to room temperature naturally, cool in an ice bath for 2h, filter, and dry to obtain the product.
[0048] The presen...
Embodiment 3
[0052] Example 3: Preparation of 2,6-dichloro-9-(3',5'-di-O-benzoyl-2'-fluoro-β-D-arabinofuranosyl)-purine (compound III)
[0053] Dissolve 12.0 g of the compound prepared in Example 1 in 100 mL of dichloromethane solution, transfer it to a 500 mL three-neck flask, add 200 mL of acetonitrile, and put in 5.0 g of 2,6-dichloropurine and 0.5 g of calcium hydride in sequence under nitrogen protection , Put 1.25g of sodium hydride into the reaction flask, and stir at room temperature for 12-16h. TLC: Ethyl acetate: Petroleum ether = 1:4, the reaction is complete, filter, wash the filter cake with a small amount of dichloromethane, adjust the pH of the filtrate to 6-8 with glacial acetic acid, filter again if there is precipitation, concentrate the mother liquor to dryness, add 20 mL of ethyl acetate The ester was heated to dissolve, and 20 mL of methanol was added while it was hot, and cooled to crystallize. After cooling down to room temperature naturally, it was cooled in an ice ...
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